The present invention relates to a sustained release pharmaceutical preparation and a process for preparing the same, and more particularly to a sustained release pharmaceutical preparation which releases a medicinal compound at a dissolution rate suitable for the medicinal compound and a process for easily and efficiently preparing the same.
Hitherto, a pharmaceutical preparation wherein a core containing a medicinal compound is coated around its surface with a hydrophobic material such as fat and oil or wax, has been known as a sustained release pharmaceutical preparation which releases a medicinal compound gradually.
Such sustained release pharmaceutical preparation comprises a core containing a medicinal compound as an effective ingredient and a coating layer containing a hydrophobic material around the core for controlling the dissolution of the medicinal compound.
The above-mentioned core and coating layer are usually prepared by separate processes respectively. That is, the core containing a medicinal compound is prepared by the usual process such as wet granulation or dry granulation and then the coating layer is provided thereon by another process with another equipment.
Various techniques have been reported with respect to processes for preparing the coating layer which controlls dissolution rate of an effective ingredient. As processes for preparing the coating layer containing a hydrophobic material, the following processes have been known.
As a general process, a hydrophobic solid material is dissolved in an organic solvent and then the obtained solution is sprayed on the surface of a core containing a medicinal compound followed by drying to coat the solid particle with the hydrophobic solid material. In such method, however, a halogenated hydrocarbon such as carbon tetrachloride or chloroform, a hydrocarbon such as hexane or benzene, a lower alcohol such as methanol or propanol, a ketone such as acetone and the like which are harmful to human body, are usually used as an organic solvent. Therefore, considerable equipments are required to secure the safety of workmen and to prevent air pollution as to the preparation of sustained release pharmaceutical preparations. Furthermore, considerable equipments and time are also required to remove the above-mentioned solvents from coated pharmaceutical preparations. Nevertheless there still remain the organic solvents in the pharmaceutical preparations.
In order to solve the above-mentioned problems, there is proposed a powder coating process wherein fine particles of a hydrophobic solid material are spread on the surface of a core containing a medicinal compound while rolling the core with spraying an aqueous solution of a binder such as methylcellulose which is a polymer compound soluble in water or an alcohol, thereby the hydrophobic solid material adhering to the core, in Japanese Unexamined Patent Publications No. 99009/1988 and No. 27424/1988. In this method, the amount of an organic solvent to be used is considerably reduced in comparison with that in the method wherein a hydrophobic material is coated by spraying an organic solvent solution thereof, or such organic solvents are not required. However, there still remain problems concerning equipments and time required in drying step and concerning the safety on using organic solvents, because water or organic solvents are still used.
As a process for coating a hydrophobic material such as fat and oil or wax without using water nor any organic solvent, there is a fused coating process. As one of a fused coating process, there is known a process wherein a heat-meltable material is molten with heating and then sprayed for coating. However, this process requires a melting pot and pipes, nozzles and the like which can be kept high temperature as equipments for coating the molten heat-meltable material. In addition, the workability is low in this process.
On the other hand, there is known a process wherein powder of a heat-meltable material is spread on powder or tablets and the mixture is rolled with heating to coat the powder or tablets with the heat-meltable material in Japanese Examined Patent Publication No. 3789/1965, as a process for coating powder or tablets with a heat-meltable material on their surface. According to this process, the coating can be carried out without using organic solvent at all nor requiring particular pipe arrangement. As a process for forming a dissolution-controlling coating layer which utilizes the above-mentioned process, there discloses a process wherein a core containing theophylline as a medicinal compound and a heat-meltable material such as wax are rolled with heating and after the heat-meltable material is molten, hydrophobic fine powder such as calcium stearate is spread, thereby the hydrophobic fine powder adhering to the core in Japanese Unexamined Patent Publication No. 171918/1982. In this process, a heat-meltable material and fine powder of a hydrophobic material are added separately without mixing. Therefore, operations are complicated and there remains a problem in uniformity of the dissolution-controlling coating layer.
On the other hand, as processes which further simplify the preparation of a sustained release pharmaceutical preparation, there disclose processes wherein two steps, namely a step of preparing a core containing a medicinal compound as an effective ingredient using a heat-meltable bead and a step of forming a coating layer thereon for controlling the dissolution of the medicinal compound, are carried out successively in Japanese Unexamined Patent Publications No. 214333/1983 and No. 181214/1987. In these processes, while the surface of the heat-meltable bead is molten in fluidized-bed granulator with heating, a medicinal compound is added to the above-mentioned heat-meltable bead which serves as a carrier, thereby the medicinal compound adhering to the carrier to give core containing an effective ingredient. Successively thereto is added a water-insoluble material such as talc while fluidizing the core with heating, thereby the water-insoluble material adhering thereto to form a coating layer for controlling the dissolution of the medicinal compound. However, in these processes, the total amount of the medicinal compound and a water-insoluble material which adheres to the heat-meltable bead is limited because they successively adhere to the molten surface of the heat-meltable bead. That is, it is difficult to freely increase the amounts of a medicinal compound and a water-insoluble material and therefore it is understood that the above-mentioned processes are not suitable for controlling the dissolution rate of the medicinal compound of a sustained release pharmaceutical preparation by increasing or decreasing the coating amount of the water-insoluble material. Furthermore, in the above-mentioned processes, strict control of the temperature is required during the process, because powder adheres to a heat-meltable bead while the heat-meltable bead gradually melts from its surface.
An object of the invention is to provide a sustained release pharmaceutical preparation whose release of a medicinal compound is accurately controlled suitably for the medicinal compound, and a simple process for safely preparing the sustained release pharmaceutical preparation which does not require organic solvents, by solving the above-mentioned problems in processes wherein organic solvents are not used and in processes wherein a core containing an effective ingredient and a coating layer for controlling the release of the effective ingredient are prepared successively.